Complex inheritance is the most common mode of genetic transmission of human disease, including diseases resulting in blindness. Despite this fact, little is known about the types of biological interactions involved in complex inheritance. Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disease for which ten causative genes have been identified. A primary component of the BBS phenotype is blindness resulting from degeneration of the photoreceptor cells of the retina. Although BBS was originally considered to be an autosomal recessive disease, it has been hypothesized and some evidence supports the idea that BBS is a complex disorder. One prominent hypothesis is that penetrance of BBS requires two mutant alleles at one locus and a third mutant allele at a second locus. Although currently considered to occur in BBS, definitive experiments regarding the prevalence of this mode of inheritance have not been performed. Furthermore, it has been recognized that patients with BBS display variable expressivity, supporting the concept that genetic modifiers play a role in the disorder. The identification of ten BBS genes provides a valuable opportunity to study complex inheritance. In this application, the most likely BBS genetic interactions involving the currently known genes will be identified through gene expression knockdown experiments in zebrafish. The nature of these interactions will be explored initially in zebrafish, and subsequently in mouse models. In addition, the effects of potential BBS interactions and modifier genes will be evaluated in human populations. The resources to successfully perform the proposed experiments have been developed in the previous funding period, and include zebrafish assays, mouse models for six different individual BBS genes, and a valuable human population segregating two different mutant BBS genes. The successful completion of the aims of this proposal will result in valuable information and resources including an improved understanding of complex inheritance in general, knowledge of key genetic interactions involved in BBS-associated retinal degeneration, improvement of recurrence risk counseling for BBS patients and their families, and novel animal models for the further study of complex inherited diseases. Mechanisms that are determined to play a role in the genetic complexity of BBS will likely provide insight into the complex inheritance of more common eye disorders, as well as obesity, hypertension and diabetes.